The most common (1/1000 live births) severally disabling birth defect in the United States is neural tube defects (NTDs). The causes of NTDs are unknown and are likely to be a result of complex interactions between genetic and environmental factors. Maternal effects or imprinting may also be involved. The Neural Tube Defects Collaborative Study serves as a rich resource for genetic studies of NTDs, with detailed phenotypic, genetic and environmental risk factor data collected on over 1000 families. To effectively dissect the underlying genetic etiology of NTDs in this study, multiple analytic approaches must be utilized including directed candidate gene studies and positional cloning. Current statistical methods for candidate gene studies fail to take full advantage of the family structure available in the NTD dataset. Specifically, in the case of NTDs and other birth defects, additional unaffected siblings are often ascertained. The log-linear model is a regression-based model, well suited for studying diseases with multifactorial etiology. However, potentially valuable data from unaffected siblings cannot be incorporated into the current model. The first goal of the proposal is to extend the log-linear model by utilizing genotype information from unaffected siblings to improve inference of missing parental data with the Expectation Maximization algorithm and to use the resulting log-linear model to test for association in NTD candidate genes. Secondly, a positional cloning strategy has never before been employed in the study of NTDs, primarily due to the paucity of multiplex families. Linkage analyses and conditional linkage analyses of the first genomic screen of NTD to date will be performed, taking advantage of the wealth of genetic and environmental data from the NTD collaborative study. A synthesis of these approaches is warranted for elucidating the etiology of NTDs.